Sarcoma is a cancer of the soft tissue (muscle, fat, nerve, or connective tissue) or bone. Sarcomas encompass a group of over 40 different types of tumors. In general, sarcomas are considered quite rare, accounting for less than 1% of all adult cancer diagnoses, with approximately 10,000 new cases annually in the soft tissues and 2,400 new cases annually in the bone. Sarcomas are considered mesenchymal cancer arising either primarily from bone cancers (different from bone metastases from other cancers), or from soft tissues such as muscle (rhabdomyosarcoma), fat tissue (liposarcoma) or smooth muscle cells (leiomyosarcoma). They are named based on the tissue from which they arise. For example, chondrosarcomas arise from cartilage, osteosarcomas arise from bone, and fibrosarcomas arise from fibrogenic tissue.
Osteosarcoma is the most common type of bone sarcoma, accounting for approximately 35% of bone tumors. Chondrosarcoma is the second most common type in adults (accounting for 30% of bone sarcomas), and Ewing's sarcoma is the second most common type in children. All other types are extremely rare, each accounting for less than 1% of all bone sarcomas. Within these types, there are further histological subtypes—for example, there are seven different types of osteosarcomas (see, www.cancer.gov/cancertopics/pdq/treatment/osteosarcoma/HealthProfessional/page4).
Oncolytic viruses are viruses selectively or preferentially infecting and killing transformed cells while sparing normal tissues. In addition to the oncolytic effect observed both in vitro and in vivo, these viruses also provide immune-stimulatory signals inducing the elimination of virus-infected tumor cells. Thereby the innate and adaptive immune systems gain access to tumor antigens, which results in cross-priming and vaccination effects.
A systematic preclinical evaluation of oncolytic virotherapy approaches for osteosarcoma treatment had been performed using the two wild type viruses Semliki Forest virus (SFV), (1), and Seneca Valley Virus (SVV, NTX-010®), (2). In a pre-clinical pediatric screening approach six osteosarcoma xenograft SCID mouse models only low treatment response was observed for the intravenous treatment with Seneca Valley Virus (SVV i.e. NTX-10®). Only one out of six xenograft models showed significantly extended event-free survival (EFS) in the treated mice—whereas data on OS were not shown (2). The second wild type virus, SFV, was shown to significantly increase survival in both a subcutaneous and a second ortho-topic osteosarcoma xenograft model in nude mice (1). Additionally two recombinant adenoviruses re-targeted to osteosarcoma were tested (3, 4). Intratumoral injections of Ad5-Delta24RGD into established human osteosarcoma xenografts refractory to chemotherapeutic treatment caused a significant tumor-growth delay (5). Another conditionally replicating adenovirus based on Ad5Delta24, Ad-OC-E1a, expresses the viral E1A gene under the control of the promoter of the bone matrix protein osteocalcin which targets Ad-OC-E1a replication to cells of the bone matrix and malignant cells derived thereof. Intravenous application of Ad-OC-E1a significantly reduced the size of pulmonary metastatic osteosarcoma nodules in a xenograft mouse model (6).
Ewing's sarcoma can occur in the bone or soft tissue (called extra-osseous), and this is important when treatment options are considered. The large majority of cases occur in the bones, and the diagnosis is most common in the teenage years. PNET (primitive neuroectodermal tumor) is a type of sarcoma closely related to Ewing's. PNET can occur in the bone or the central nervous system. PNET of the bone is treated the same as Ewing's sarcoma, but PNET in the brain or spinal cord is a genetically different tumor that is treated differently. Ewing's, PNET, Askin's tumors and neuroepithelioma all contain the same genetic abnormality, called an 11-22 chromosomal translocation (t11;22). Because of this similarity, these tumors are referred to as the Ewing's sarcoma family of tumors and are treated similarly.
Few therapeutic attempts based on oncolytic viruses have been reported for Ewing's sarcoma so far. The genetically engineered oncolytic HSVs NV1020 and G207 had also been tested on a panel of ten sarcoma cell lines. However, compared to RMS and osteosarcoma cell lines Ewing's sarcoma cell lines showed the lowest susceptibility to oncolytic HSVs in vitro (7). The susceptibility of Ewing's sarcoma cell lines to adenovirus-mediated transduction could also be demonstrated, since the expression of adenovirus-receptor and Coxsackie-adenovirus-receptor was observed on these cell lines. Moreover, a recombinant conditionally replicating adenovirus induced significant oncolytic effects on Ewing's sarcoma cell lines in vitro (8). In animal models only two oncolytic viruses were tested: the wild type virus SVV and a recombinant AAV expressing an anti-angiogenic soluble VEGF-ligand. Both viruses could not be shown to be therapeutically effective. A preventive intravenous application of a rAAV expressing an anti-angiogenic soluble VEGF-ligand into the portal vein of SCID mice prevented the subsequent engraftment of Ewing's sarcoma xenografts (10). In four Ewing's sarcoma xenograft models the systematic preclinical evaluation of SVV did not induce any significant therapeutic effects (2). So far no application of rodent parvoviruses to Ewing's sarcoma has been described.
Typically, current treatment of bone sarcoma is multimodal and risk-adapted according to the therapy study EURAMOS1 (for osteosarcoma) of the GPOH including neo-adjuvant polychemo-therapy, tumor resection and radiotherapy. According to EWING 2008 high risk (R2 and R3) Ewing's sarcoma patients receive high dose chemotherapy in combination with the transplantation of autologous stem cells. In principle, radiation and intravenous drips of cytotoxic chemicals are used in combination. The side effects, both short term and long term, can be harsh. Short term negative side effects of chemotherapy include loss of hair and eyebrows, loss of appetite, having food taste peculiar, mouth sores, nausea, vomiting, loose stools or constipation (due to less food intake), fatigue, mental fogginess and inability to resist infections. Another short term disadvantage is that treatment is time-consuming. Long term side effects (depending on the type of cancer) include infertility, heart problems, damage to the central nervous system or damage to vital organs such as the lungs or liver.
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